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In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non\u2010diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55\u2009mL\/min), hyperfiltration of remnant nephrons, elevated albuminuria (500\u2009mg\/day), and minimal levels of urinary glucose (0.02\u2009mmol\/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12\u2009months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes.<\/jats:p>","DOI":"10.14814\/phy2.15836","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T22:29:26Z","timestamp":1699914566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Modeling the renoprotective mechanisms of\n                    <scp>SGLT2<\/scp>\n                    inhibition in hypertensive chronic kidney disease"],"prefix":"10.14814","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2250-2960","authenticated-orcid":false,"given":"John S.","family":"Clemmer","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitsugu","family":"Obi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2030186"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000499486"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00528.2022"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(17)30182-1"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00353.2016"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0259917"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10113146"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.7326\/AITC201506020"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.120.000408"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP202929"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2014.02.013"},{"key":"e_1_2_8_13_1","volume-title":"Arterial pressure and hypertension","author":"Guyton A. 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